Devising procedures for specifically suppressing immunity for transplanation or treating autiommunity and for rescuring suppressed immunity to cancer is a major challenge for immunologists. Expectations have been high that these objectives will be obtained using only specific reactants: antigens and antibodies or lymphocytes having idiotypic or anti-idiotypic specificities. But specific immunity may be profoundly, possibly primarily, regulated by nonspecific components of the system. One kind of evidence for this possibility derives from work on regulation of dendritic cells (DC) (which have interacted with antigen) by activated Thy1- natural killer (NK) cells. Other evidence comes from observations on nonspecific suppressor cells (NS) which are isolated from tissues during generation or regeneration of lympho-hematopoietic tissue, and possibly from observations on suppressor cells which are induced in vitro by culturing normal cells alone (CIS). Thus, one major objective of this proposal is concerned with the regulation of antigen presentation by DC; the other major objective is concerned with modulation of immunity by NS/CIS. For the first objective, we will determine the requirements of subpopulations of T lymphocytes for DC in vivo and how activation of NK cells or elimination of NK cells affects these responses. We will also determine how agents or procedures which affect DC function independent of NK cells alter T cells responses. In almost all studies related to the second objective, NS/CIS are Ly2-, L3T4-, sIg-, Ia-, and usually AGMI-; however, there is no agreement whether the cells are Thyl- or Thyl+ (which is directly related to the question of whether the cells are CD3+ and have rearranged genes for the gamma and delta chains of the T cell receptor). Also there is disagreement on whether the cells are H2 restricted or unrestricted, adherent or nonadherent, radiosensitive or radioresistant. If is also not known whether NS/CIS from the same or different tissues have common or different lineages or in fact whether NS/CIS from any one source represent a single cell type. Thus, the second objective is to determine the cellular origin of NS/CIS, the targets for NS/CIS, and how NS/CIS suppress. Both objectives require preparing homogeneous populations of subsets of lymphocytes and other cell types for assaying the interactions of these populations in vitro and in vivo. The proposed studies should provide new insight in a field of immunologic research which may lead to procedures for regulating the host's immune response to transplants and tumors, and in autiommune disease.